US7964749B2 - Process for obtaining valine derivatives useful for obtaining a pharmaceutically active compound - Google Patents
Process for obtaining valine derivatives useful for obtaining a pharmaceutically active compound Download PDFInfo
- Publication number
- US7964749B2 US7964749B2 US12/090,729 US9072906A US7964749B2 US 7964749 B2 US7964749 B2 US 7964749B2 US 9072906 A US9072906 A US 9072906A US 7964749 B2 US7964749 B2 US 7964749B2
- Authority
- US
- United States
- Prior art keywords
- process according
- compound
- formula
- valine
- chosen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
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- 238000000034 method Methods 0.000 title claims abstract description 53
- 230000008569 process Effects 0.000 title claims abstract description 44
- 150000001875 compounds Chemical class 0.000 title claims abstract description 33
- 150000003679 valine derivatives Chemical class 0.000 title 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims abstract description 46
- 229960004295 valine Drugs 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 150000007530 organic bases Chemical class 0.000 claims abstract description 16
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims abstract description 15
- 229960004699 valsartan Drugs 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 230000006181 N-acylation Effects 0.000 claims abstract description 7
- 230000009467 reduction Effects 0.000 claims abstract description 7
- 239000002798 polar solvent Substances 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 238000007866 imination reaction Methods 0.000 claims abstract description 5
- 238000005580 one pot reaction Methods 0.000 claims abstract description 5
- 125000003944 tolyl group Chemical group 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 5
- 150000001768 cations Chemical class 0.000 claims abstract description 4
- 125000003172 aldehyde group Chemical group 0.000 claims abstract description 3
- 125000000879 imine group Chemical group 0.000 claims abstract description 3
- 230000020477 pH reduction Effects 0.000 claims abstract description 3
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims abstract 2
- 230000015572 biosynthetic process Effects 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000003786 synthesis reaction Methods 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 150000004753 Schiff bases Chemical class 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003863 metallic catalyst Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 5
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002262 Schiff base Substances 0.000 claims description 3
- 239000000852 hydrogen donor Substances 0.000 claims description 3
- 239000002609 medium Substances 0.000 claims description 3
- 239000003586 protic polar solvent Substances 0.000 claims description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000002883 imidazolyl group Chemical group 0.000 claims 1
- 229960004592 isopropanol Drugs 0.000 claims 1
- 229910052697 platinum Inorganic materials 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 206010019280 Heart failures Diseases 0.000 abstract description 2
- 208000037849 arterial hypertension Diseases 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 16
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 150000003536 tetrazoles Chemical class 0.000 description 7
- PVYXSCVNHRMWIN-UHFFFAOYSA-N CCCCC(=O)N(CC1=CC=C(C)C=C1)C(C(=O)O)C(C)C Chemical compound CCCCC(=O)N(CC1=CC=C(C)C=C1)C(C(=O)O)C(C)C PVYXSCVNHRMWIN-UHFFFAOYSA-N 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 0 CCCCC(N(Cc1ccc(*)cc1)C(C(C)C)C(O)=O)=O Chemical compound CCCCC(N(Cc1ccc(*)cc1)C(C(C)C)C(O)=O)=O 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- JLSJNULDXGXFBC-NSHDSACASA-N (2s)-2-[(4-bromophenyl)methylazaniumyl]-3-methylbutanoate Chemical compound CC(C)[C@@H](C(O)=O)NCC1=CC=C(Br)C=C1 JLSJNULDXGXFBC-NSHDSACASA-N 0.000 description 3
- HPARGISGLZSZOG-XHIXCECLSA-M CC1=CC=C(/C=N/C(C(=O)[O-])C(C)C)C=C1.[BH2+] Chemical compound CC1=CC=C(/C=N/C(C(=O)[O-])C(C)C)C=C1.[BH2+] HPARGISGLZSZOG-XHIXCECLSA-M 0.000 description 3
- XWDMATYLELXQKK-UHFFFAOYSA-N CC1=CC=C(CNC(C(=O)O)C(C)C)C=C1 Chemical compound CC1=CC=C(CNC(C(=O)O)C(C)C)C=C1 XWDMATYLELXQKK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- LCRCBXLHWTVPEQ-UHFFFAOYSA-N 2-phenylbenzaldehyde Chemical compound O=CC1=CC=CC=C1C1=CC=CC=C1 LCRCBXLHWTVPEQ-UHFFFAOYSA-N 0.000 description 2
- IJIBRSFAXRFPPN-UHFFFAOYSA-N 5-bromo-2-methoxybenzaldehyde Chemical compound COC1=CC=C(Br)C=C1C=O IJIBRSFAXRFPPN-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- MQUSOWYDELDFBC-INIZCTEOSA-N (2s)-2-[(4-bromophenyl)methyl-pentanoylamino]-3-methylbutanoic acid Chemical compound CCCCC(=O)N([C@@H](C(C)C)C(O)=O)CC1=CC=C(Br)C=C1 MQUSOWYDELDFBC-INIZCTEOSA-N 0.000 description 1
- RQMWVVBHJMUJNZ-UHFFFAOYSA-N 4-chloropyridin-2-amine Chemical group NC1=CC(Cl)=CC=N1 RQMWVVBHJMUJNZ-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- IXSKTUCVQIZZIY-UHFFFAOYSA-L C.CC(C)C(N)C(=O)O.CC1=CC=C(C=O)C=C1.I[V]I Chemical compound C.CC(C)C(N)C(=O)O.CC1=CC=C(C=O)C=C1.I[V]I IXSKTUCVQIZZIY-UHFFFAOYSA-L 0.000 description 1
- XNUNFARZVOHMKC-HXEJHZAHSA-F CC(C)C(N)C(=O)O.CC1=CC=C(/C=N/C(C(=O)[O-])C(C)C)C=C1.CC1=CC=C(C=O)C=C1.CC1=CC=C(CNC(C(=O)O)C(C)C)C=C1.CCCCC(=O)Cl.CCCCC(=O)N(CC1=CC=C(C)C=C1)C(C(=O)O)C(C)C.II.I[V](I)I.I[V]I.[BH2+].[V]I.[V]I Chemical compound CC(C)C(N)C(=O)O.CC1=CC=C(/C=N/C(C(=O)[O-])C(C)C)C=C1.CC1=CC=C(C=O)C=C1.CC1=CC=C(CNC(C(=O)O)C(C)C)C=C1.CCCCC(=O)Cl.CCCCC(=O)N(CC1=CC=C(C)C=C1)C(C(=O)O)C(C)C.II.I[V](I)I.I[V]I.[BH2+].[V]I.[V]I XNUNFARZVOHMKC-HXEJHZAHSA-F 0.000 description 1
- QGOPPXDRHGEYRZ-UHFFFAOYSA-K CC(C)C(N)C(=O)O.CC1=CC=C(CC=O)C=C1.I[V]I.[V]I Chemical compound CC(C)C(N)C(=O)O.CC1=CC=C(CC=O)C=C1.I[V]I.[V]I QGOPPXDRHGEYRZ-UHFFFAOYSA-K 0.000 description 1
- SETWKWACNLFVCZ-UHFFFAOYSA-M CC1=CC=C(CNC(C(=O)O)C(C)C)C=C1.CCCCC(=O)Cl.[V]I Chemical compound CC1=CC=C(CNC(C(=O)O)C(C)C)C=C1.CCCCC(=O)Cl.[V]I SETWKWACNLFVCZ-UHFFFAOYSA-M 0.000 description 1
- YEBOADXQCFDFJU-UHFFFAOYSA-N CCCCC(=O)N(CC1=CC=C(C)C=C1)C(C(=O)O)C(C)C.CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)C(C(=O)O)C(C)C.I.II.I[IH]I.OB(O)C1=CC=CC=C1C1=NN=NN1 Chemical compound CCCCC(=O)N(CC1=CC=C(C)C=C1)C(C(=O)O)C(C)C.CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)C(C(=O)O)C(C)C.I.II.I[IH]I.OB(O)C1=CC=CC=C1C1=NN=NN1 YEBOADXQCFDFJU-UHFFFAOYSA-N 0.000 description 1
- SKLLEVBYOXINGN-UHFFFAOYSA-K CCCCC(=O)N(CC1=CC=C(C)C=C1)C(C(=O)O)C(C)C.CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)C(C(=O)O)C(C)C.I.I[V]I.OB(O)C1=CC=CC=C1C1=NN=NN1.[V]I Chemical compound CCCCC(=O)N(CC1=CC=C(C)C=C1)C(C(=O)O)C(C)C.CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)C(C(=O)O)C(C)C.I.I[V]I.OB(O)C1=CC=CC=C1C1=NN=NN1.[V]I SKLLEVBYOXINGN-UHFFFAOYSA-K 0.000 description 1
- RRSMVWBQXXLKHP-UHFFFAOYSA-N CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C)C=C1)C(C)C(C)C Chemical compound CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C)C=C1)C(C)C(C)C RRSMVWBQXXLKHP-UHFFFAOYSA-N 0.000 description 1
- ACWBQPMHZXGDFX-UHFFFAOYSA-N CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)C(C(=O)O)C(C)C Chemical compound CCCCC(=O)N(CC1=CC=C(C2=CC=CC=C2C2=NN=NN2)C=C1)C(C(=O)O)C(C)C ACWBQPMHZXGDFX-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 1
- GVRXWYFECKHTSJ-UHFFFAOYSA-N [2-(2h-tetrazol-5-yl)phenyl]boronic acid Chemical compound OB(O)C1=CC=CC=C1C1=NNN=N1 GVRXWYFECKHTSJ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000003855 acyl compounds Chemical class 0.000 description 1
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
Definitions
- the present invention relates to a method for obtaining intermediates useful for obtaining a pharmaceutically active compound for manufacturing a drug for the treatment of arterial hypertension or heart failure.
- the present invention relates to a method for obtaining intermediates useful in the synthesis of Valsartan.
- Said Spanish patent describes the preparation of Valsartan by converting a phenyl substituent (Z 1 ) into tetrazole, where Z 1 is a group convertible into tetrazole.
- Z 1 is a group convertible into tetrazole.
- the examples of said patent describe the specific case in which Z 1 is a cyano group or a protected tetrazole ring. This is followed by final deprotection of the carboxylic acid group, where R is preferably methyl or benzyl and, if this is the case, of the tetrazole ring protecting group, preferably a trityl group.
- Another negative aspect lies in the use of bulky protective groups both for the tetrazole ring (trityl group) and the carboxylic acid of the valine moiety (benzyl group), which very considerably increase the molecular weight of the last synthesis intermediate. This molecular weight is drastically reduced in the final hydrolysis to give Valsartan, thus resulting in a process of low atomic efficiency. This further creates a considerable amount of residues and increases the number of synthesis steps in the process.
- Patents DE4313747, DE4407488, U.S. Pat. No. 5,596,006, EP594022 and WO9609301 describe the synthesis of sartans by formation of the biphenyl system by reacting an aryl halide with 2-(1H-tetrazol-5-yl)phenylboronic acid in the presence of a palladium catalyst.
- European patent application EP1533305 describes a method for obtaining Valsartan by means of reductive amination reaction of a biphenyl aldehyde with protected L-valine with a benzyl group which has to be eliminated.
- the tetrazole group is formed in the penultimate step of the synthesis.
- Valsartan that is safe, ecological and with high yields and few synthesis steps and from simple and commercially available starting products. Additionally, it must be possible to apply the process on an industrial scale and to avoid racemisation and the consequent separation of enantiomers.
- Patent application ES200400949 describes a process for the synthesis of Valsartan that includes reaction of the intermediate (II) with a boronic acid of formula (III) in order to give Valsartan (I):
- Preparation of the Intermediate (II), in accordance with patent application ES200400949, comprises: a) alkylation of the L-Valine (IV) with a halide of formula (V) to give a compound of formula (VI) followed by b) acylation with valeryl chloride.
- the carboxylic acid In the alkylation step the carboxylic acid must be protected in the form of silyl ester to prevent the formation of the benzyl ester. Furthermore, the dialkylation compound in the nitrogen of the L-Valine is inevitably formed in variable proportions and is difficult to eliminate.
- reaction conditions are critical, and a restricted range of reaction parameters has to be used in order to prevent partial racemisation of compound (II) that would involve additional purifications.
- a first aspect of the present invention is to provide an industrially viable process for obtaining the synthesis intermediate (II), useful in the preparation of Valsartan, and permitting it to be obtained with high yields and without racemisation.
- a second aspect of the invention is to provide a method for obtaining the synthesis intermediate (II) with few synthesis steps.
- work up is taken to mean the work of isolation and/or purification that is carried out once the reaction has finished. This involves, for example, extractions or precipitations in an aqueous medium.
- one pot is taken to mean a series of consecutive reactions that are carried out without isolating the respective intermediates.
- the object of the present invention is to provide a new process for obtaining the intermediate of formula (II), that permits it to be obtained with good yields, without racemisation, free from impurities and without problematic safety and environmental aspects.
- X means halogen or an —OSO 2 R group, where R is CF 3 , tolyl, methyl or F;
- X has the meaning defined above and B + is the protonated form of an organic base or an alkaline cation.
- the process according to the invention does not use protective groups of the carboxylic acid group of the valine moiety in preparation of the synthesis intermediate (VI).
- This is advantageous for what is understood as the atomic efficiency of the process, i.e. the proportion of atoms of the respective starting reagents that are incorporated into the desired product is optimum, and this translates into a considerable reduction of the amount of residues to be treated.
- step a) the intermediate of formula (VIII) is obtained:
- X means halogen or an —OSO 2 R group, where R is CF 3 , tolyl, methyl or F, and B + is the protonated form of an organic base or an alkaline cation, by means of an imination reaction of a benzaldehyde substituted in the position for (VII) by salts of the L-Valine with organic or inorganic bases.
- the L-Valine is mixed with the 4-substituted benzaldehyde (VII) in the presence of an organic or inorganic base in equimolar proportion in relation to the L-Valine and a polar solvent or water at a temperature between 0° C. and the boiling temperature of the solvent, preferably between 10° C. and 35° C.
- a substituted amine-type organic base may be used, such as triethylamine, trialkylamine, diisopropylethylamine (DIPEA) or a metallic alcoxide or hydroxide to form a salt of the L-Valine with an alkaline metal.
- DIPEA diisopropylethylamine
- the salt of an alkaline metal of the L-Valine can be prepared in situ in the reaction medium by the addition of bases such as hydroxides and alcoxylates, for example sodium hydroxide, potassium hydroxide, sodium methylate or sodium ethylate in a solution in methanol and optionally water.
- bases such as hydroxides and alcoxylates, for example sodium hydroxide, potassium hydroxide, sodium methylate or sodium ethylate in a solution in methanol and optionally water.
- the sodium salt can also be prepared independently by addition of a metal in elemental state, such as metallic sodium, to a solution of L-Valine in a polar solvent in the absence of water, such as anhydrous methanol.
- the solvent of the reaction can be selected between water or a protic polar solvent.
- the protic polar solvent is an alcohol, such as methanol, ethanol, 2-propanol, but more preferably methanol.
- step b) the intermediate (VIII) is submitted to reductive conditions to obtain the compound (VI).
- the reaction takes place in an alcoholic medium using borohydride as reducing agent, such as sodium borohydride, lithium borohydride, calcium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.
- borohydride as reducing agent, such as sodium borohydride, lithium borohydride, calcium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.
- the reduction can also be carried out by means of catalytic hydrogenation in the presence of hydrogen and of a metallic catalyst at atmospheric pressure, or by transfer of hydrogen in the presence of a metallic catalyst and a hydrogen donor such as formic acid, 2-propanol, ethanol, etc.
- the metallic catalyst used can be Raney-Nickel or a palladium, rhodium or ruthenium catalyst, preferably a palladium catalyst.
- the reduction is carried out with sodium borohydride.
- racemisation of the chiral centre present in the molecule is prevented. This is an additional advantage over methods that involve the utilisation of carboxylic group protective groups, since the deprotection conditions can lead to racemisation.
- This process has the advantage that it does not require protection of the carboxyl group of the L-Valine.
- the reductive amination reaction has the additional advantage of preventing formation of the dialkylation product.
- step c) the compound (VI) obtained is made to react with valeryl chloride in order to provide the intermediate (II):
- X means halogen or an —OSO 2 R group, where R is CF 3 , tolyl, methyl or F.
- This step c) of the process is characterised in that it consists in N-acylation of the compound of formula (VI) with valeryl chloride, without the protection of carboxylic acid:
- said aprotic organic solvent is selected from tetrahydrofuran (THF), dimethoxyethane (DME) and acetonitrile. More preferably still, it is tetrahydrofuran (THF).
- an organic base will be selected from a heterocyclic compound that contains one or more atoms of nitrogen.
- said heterocyclic compound with at least one atom of nitrogen is chosen from pyridine or pyridines substituted with one or more methyl groups, such as collidines or lutidines; or imidazole or imidazole substituted with a methyl group such as 2-methylimidazole or 4-methylimidazole. More preferably still, 2-methylimidazole is used.
- step c) takes place in the presence of 1 or 2 equivalents of water in relation to the amount of starting product (VI).
- the presence of water in said reaction prevents racemisation of the asymmetric carbon.
- said N-acylation is carried out at a temperature between ⁇ 10 and 10° C.
- a method for obtaining the synthesis intermediate (II) with few synthesis steps, where the compound of formula (VI) can be obtained by means of a one-pot reaction from the starting products (VII) and (IV), without need to isolate the imine compound (VIII).
- the compound of formula (II) is achieved with good yields and in two reaction steps, since the one-pot reaction is carried out according to the conditions set out in steps a) and b) to obtain the compound of formula (VI) from simple and commercially available raw materials.
- the product obtained according to the first or second aspects of the invention can be purified by conventional methods such as recrystallisation in a single solvent or in a mixture of a solvent and antisolvent, for example ethanol/water, ethyl acetate/hexane, dichloromethane/heptane, isopropyl acetate/methylcyclohexane.
- a solvent and antisolvent for example ethanol/water, ethyl acetate/hexane, dichloromethane/heptane, isopropyl acetate/methylcyclohexane.
- the invention provides a method for obtaining the intermediate of formula (II) without racemisation from a compound of formula (VI) that does not require the protection of the carboxylic acid.
- the compound of formula (VI) is obtained with an optical purity of 99.5-100%.
- Valsartan is obtained with good chemical yield and high optical purity by means of a process applicable on an industrial scale and starting from simple and commercially available products through synthesis intermediates that do not require protection of the tetrazolic ring or of the carboxylic acid of the L-Valine moiety, nor the use of sodium azide or tributyl tin azide, thereby improving the safety of the process and reducing its environmental impact.
- a mixture formed by 11.4 g (40 mmol) of N-(4-bromobenzyl)-L-Valine and 60 mL of THF is cooled to ⁇ 5° C., and 2.8 mL (50 mmol) of HAcO, 7.6 mL (64 mmol) of valeryl chloride and a solution of 4.9 g (60 mmol) of 2-methylimidazole in 30 mL of THF and 1.4 mL (80 mmol) of H 2 O are added to it.
- the reaction mixture is stirred for 30 minutes at room temperature, 10 mL of methanol is added to it, it is then stirred for a further 15 minutes and 40 mL of H 2 O is added to it.
- the phases are separated and the organic phase is evaporated to dryness and the solid obtained is recrystallised from a mixture of EtOH:H 2 O 1:1.
- Example 5 In a manner similar to Example 5 and starting from 12 g (32 mmol) of N-(4-tosylbenzyl)-L-Valine, 6.2 mL (51 mmol) of valeryl chloride and 3.95 g (48 mmol) of 2-methylimidazole, 11 g (75%) of N-(4-toluen-4-sulphonyl)-benzyl)-N-valeryl-L-Valine is obtained. The solid is recrystallised from a mixture of n-Heptane:EtAcO 10:1.
- IR (KBr, cm-1): 2957, 1714, 1575, 1469, 1362, 1249, 1173, 1092, 862, 748, 688, 660.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200502558 | 2005-10-20 | ||
ESP-200502558 | 2005-10-20 | ||
ES200502558A ES2288376B1 (es) | 2005-10-20 | 2005-10-20 | Procedimiento para la obtencion de intermedios utiles en la obtencion de un compuesto farmaceuticamente activo. |
PCT/EP2006/067569 WO2007045675A1 (fr) | 2005-10-20 | 2006-10-19 | Procede d’obtention de derives de valine utiles pour la fabrication d’un compose pharmaceutiquement actif |
Publications (2)
Publication Number | Publication Date |
---|---|
US20100240919A1 US20100240919A1 (en) | 2010-09-23 |
US7964749B2 true US7964749B2 (en) | 2011-06-21 |
Family
ID=37603219
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/090,729 Expired - Fee Related US7964749B2 (en) | 2005-10-20 | 2006-10-19 | Process for obtaining valine derivatives useful for obtaining a pharmaceutically active compound |
Country Status (8)
Country | Link |
---|---|
US (1) | US7964749B2 (fr) |
EP (1) | EP1937654B1 (fr) |
JP (1) | JP2009512661A (fr) |
CN (1) | CN101309910A (fr) |
AT (1) | ATE448212T1 (fr) |
DE (1) | DE602006010423D1 (fr) |
ES (1) | ES2288376B1 (fr) |
WO (1) | WO2007045675A1 (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009125416A2 (fr) | 2008-04-07 | 2009-10-15 | Hetero Research Foundation | Procédé de préparation d'un intermédiaire de valsartan |
CN107987125A (zh) * | 2017-11-23 | 2018-05-04 | 爱斯特(成都)生物制药股份有限公司 | 一种缬氨酸衍生物的制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004026847A1 (fr) * | 2002-09-23 | 2004-04-01 | Novartis Ag | Procede de fabrication de valsartan |
US7439261B2 (en) * | 2003-11-21 | 2008-10-21 | Dipharma S.P.A. | Process for the preparation of valsartan and intermediates thereof |
US20090124577A1 (en) * | 2004-12-22 | 2009-05-14 | Enantia Si | Intermediate Compounds for the Preparation of an Angiotensin II Receptor Antagonist |
US7728021B2 (en) * | 2004-04-20 | 2010-06-01 | Inke, S.A. | Process for the preparation of Valsartan and precursors thereof |
-
2005
- 2005-10-20 ES ES200502558A patent/ES2288376B1/es not_active Expired - Fee Related
-
2006
- 2006-10-19 US US12/090,729 patent/US7964749B2/en not_active Expired - Fee Related
- 2006-10-19 AT AT06819100T patent/ATE448212T1/de not_active IP Right Cessation
- 2006-10-19 CN CNA2006800423423A patent/CN101309910A/zh active Pending
- 2006-10-19 JP JP2008536054A patent/JP2009512661A/ja not_active Withdrawn
- 2006-10-19 WO PCT/EP2006/067569 patent/WO2007045675A1/fr active Application Filing
- 2006-10-19 EP EP06819100A patent/EP1937654B1/fr active Active
- 2006-10-19 DE DE602006010423T patent/DE602006010423D1/de active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004026847A1 (fr) * | 2002-09-23 | 2004-04-01 | Novartis Ag | Procede de fabrication de valsartan |
US7439261B2 (en) * | 2003-11-21 | 2008-10-21 | Dipharma S.P.A. | Process for the preparation of valsartan and intermediates thereof |
US7728021B2 (en) * | 2004-04-20 | 2010-06-01 | Inke, S.A. | Process for the preparation of Valsartan and precursors thereof |
US20090124577A1 (en) * | 2004-12-22 | 2009-05-14 | Enantia Si | Intermediate Compounds for the Preparation of an Angiotensin II Receptor Antagonist |
Also Published As
Publication number | Publication date |
---|---|
EP1937654A1 (fr) | 2008-07-02 |
WO2007045675A1 (fr) | 2007-04-26 |
EP1937654B1 (fr) | 2009-11-11 |
ATE448212T1 (de) | 2009-11-15 |
ES2288376B1 (es) | 2008-11-01 |
JP2009512661A (ja) | 2009-03-26 |
DE602006010423D1 (de) | 2009-12-24 |
ES2288376A1 (es) | 2008-01-01 |
CN101309910A (zh) | 2008-11-19 |
US20100240919A1 (en) | 2010-09-23 |
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